title: Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions.
abstract: Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipocyte differentiation, and an adipogenesis-promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho-knockout mice (11.7±0.3 g at 9 wk), leptin-deficient (ob/ob) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity [ob/ob-klotho double-knockout (DKO) mice]. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild-type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob-klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob-klotho DKO mice had significantly (P<0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob-klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob-klotho DKO mice, compared to their ob/ob counterparts (ob/ob vs. ob/ob-klotho DKO: 266 ± 36 vs. 65±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high-fat-diet-induced obesity, we provided a high-fat (60%) diet to klotho-knockout mice and compared them with normal-fat (20%) diet-fed klotho-knockout mice. No significant difference in body weight was detected in klotho-knockout mice fed either the normal-fat diet or high-fat diet, while WT mice fed the high-fat diet gradually gained body weight, compared to the normal-fat-diet-fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications.
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Research and Education Bldg., 190 Longwood Ave., Boston, MA 02115, USA.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Shigeko
authors.initials: S
authors.lastname: Kato
authors.forename: Junko
authors.initials: J
authors.lastname: Akiyoshi
authors.forename: Azeddine
authors.initials: A
authors.lastname: Atfi
authors.forename: M Shawkat
authors.initials: MS
authors.lastname: Razzaque
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004041:Dietary Fats; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D047495:PPAR gamma / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D020738:Leptin; D047495:PPAR gamma; D014280:Triglycerides; D002784:Cholesterol; D005966:Glucuronidase; D000090265:Klotho Proteins; D005947:Glucose